Kevin S. Choe

ATM Kinase Inhibition Preferentially Sensitizes p53-Mutant Glioma to Ionizing Radiation

Purpose: Glioblastoma multiforme (GBM) is the most lethal form of brain cancer with a median survival of only 12 to 15 months. Current standard treatment consists of surgery followed by chemoradiation. The poor survival of patients with GBM is due to aggressive tumor invasiveness, an inability to remove all tumor tissue, and an innate tumor chemo- and radioresistance. Ataxia–telangiectasia mutated (ATM) is an excellent target for radiosensitizing GBM because of its critical role in regulating the DNA damage response and p53, among other cellular processes. As a first step toward this goal, we recently showed that the novel ATM kinase inhibitor KU-60019 reduced migration, invasion, and growth, and potently radiosensitized human glioma cells in vitro. Experimental Design: Using orthotopic xenograft models of GBM, we now show that KU-60019 is also an effective radiosensitizer in vivo. Human glioma cells expressing reporter genes for monitoring tumor growth and dispersal were grown intracranially, and KU-60019 was administered intratumorally by convection-enhanced delivery or osmotic pump. Results: Our results show that the combined effect of KU-60019 and radiation significantly increased survival of mice 2- to 3-fold over controls. Importantly, we show that glioma with mutant p53 is much more sensitive to KU-60019 radiosensitization than genetically matched wild-type glioma. Conclusions: Taken together, our results suggest that an ATM kinase inhibitor may be an effective radiosensitizer and adjuvant therapy for patients with mutant p53 brain cancers. Clin Cancer Res; 19(12); 3189–200. ©2013 AACR.

Aspirin Use and the Risk of Prostate Cancer Mortality in Men Treated With Prostatectomy or Radiotherapy

PURPOSE Experimental evidence suggests that anticoagulants (ACs) may inhibit cancer growth and metastasis, but clinical data have been limited. We investigated whether use of ACs was associated with the risk of death from prostate cancer. PATIENTS AND METHODS This study comprised 5,955 men in the Cancer of the Prostate Strategic Urologic Research Endeavor database with localized adenocarcinoma of the prostate treated with radical prostatectomy (RP) or radiotherapy (RT). Of them, 2,175 (37%) were receiving ACs (warfarin, clopidogrel, enoxaparin, and/or aspirin). The risk of prostate cancer-specific mortality (PCSM) was compared between the AC and non-AC groups. RESULTS After a median follow-up of 70 months, risk of PCSM was significantly lower in the AC group compared with the non-AC group (3% v 8% at 10 years; P < .01). The risks of disease recurrence and bone metastasis were also significantly lower. In a subgroup analysis by clinical risk category, the reduction in PCSM was most prominent in patients with high-risk disease (4% v 19% at 10 years; P < .01). The benefit from AC was present across treatment modalities (RT or RP). Analysis by type of AC medication suggested that the PCSM reduction was primarily associated with aspirin. Multivariable analysis indicated that aspirin use was independently associated with a lower risk of PCSM (adjusted hazard ratio, 0.43; 95% CI, 0.21 to 0.87; P = .02). CONCLUSION AC therapy, particularly aspirin, was associated with a reduced risk of PCSM in men treated with RT or RP for prostate cancer. The association was most prominent in patients with high-risk disease.

Isolated central nervous system progression on Crizotinib: An Achilles heel of non-small cell lung cancer with EML4-ALK translocation?

Advanced non-small lung cancer (NSCLC) remains almost uniformly lethal with marginal long-term survival despite efforts to target specific oncogenic addiction pathways that may drive these tumors with small molecularly targeted agents and biologics. The EML4-ALK fusion gene encodes a chimeric tyrosine kinase that activates the Ras signaling pathway, and this fusion protein is found in approximately 5% of NSCLC. Targeting EML4-ALK with Crizotinib in this subset of NSCLC has documented therapeutic efficacy, but the vast majority of patients eventually develop recurrent disease that is often refractory to further treatments. We present the clinicopathologic features of three patients with metastatic NSCLC harboring the EML4-ALK translocation that developed isolated central nervous system (CNS) metastases in the presence of good disease control elsewhere in the body. These cases suggest a differential response of NSCLC to Crizotinib in the brain in comparison to other sites of disease, and are consistent with a previous report of poor CNS penetration of Crizotinib. Results of ongoing clinical trials will clarify whether the CNS is a major sanctuary site for EML4-ALK positive NSCLC being treated with Crizotinib. While understanding molecular mechanisms of resistance is critical to overcome therapeutic resistance, understanding physiologic mechanisms of resistance through analyzing anatomic patterns of failure may be equally crucial to improve long-term survival for patients with EML4-ALK translocation positive NSCLC.

Prior chemoradiotherapy adversely impacts outcomes of recurrent and second primary head and neck cancer treated with concurrent chemotherapy and reirradiation.

It has been shown that concomitant chemotherapy (C) with reirradiation (ReRT) is feasible and effective for select patients with recurrent or second primary head and neck cancer (HNC). To examine potential prognostic factors associated with survival, the authors of this report retrospectively reviewed the outcomes of patients who received CReRT.

External beam radiotherapy for prostate cancer patients on anticoagulation therapy: how significant is the bleeding toxicity?

PURPOSE To characterize the bleeding toxicity associated with external beam radiotherapy for prostate cancer patients receiving anticoagulation (AC) therapy. METHODS AND MATERIALS The study cohort consisted of 568 patients with adenocarcinoma of the prostate who were treated with definitive external beam radiotherapy. Of these men, 79 were receiving AC therapy with either warfarin or clopidogrel. All patients were treated with three-dimensional conformal radiotherapy or intensity-modulated radiotherapy. Bleeding complications were recorded during treatment and subsequent follow-up visits. RESULTS With a median follow-up of 48 months, the 4-year actuarial risk of Grade 3 or worse bleeding toxicity was 15.5% for those receiving AC therapy compared with 3.6% among those not receiving AC (p < .0001). On multivariate analysis, AC therapy was the only significant factor associated with Grade 3 or worse bleeding (p < .0001). For patients taking AC therapy, the crude rate of bleeding was 39.2%. Multivariate analysis within the AC group demonstrated that a higher radiotherapy dose (p = .0408), intensity-modulated radiotherapy (p = 0.0136), and previous transurethral resection of the prostate (p = .0001) were associated with Grade 2 or worse bleeding toxicity. Androgen deprivation therapy was protective against bleeding, with borderline significance (p = 0.0599). Dose-volume histogram analysis revealed that Grade 3 or worse bleeding was minimized if the percentage of the rectum receiving >or=70 Gy was <10% or the rectum receiving >or=50 Gy was <50%. CONCLUSION Patients taking AC therapy have a substantial risk of bleeding toxicity from external beam radiotherapy. In this setting, dose escalation or intensity-modulated radiotherapy should be used judiciously. With adherence to strict dose-volume histogram criteria and minimizing hotspots, the risk of severe bleeding might be reduced.

The use of anticoagulants improves biochemical control of localized prostate cancer treated with radiotherapy

Substantial experimental evidence suggests that anticoagulants (ACs) may inhibit cancer growth and metastasis, although the limited data from clinical trials have been inconsistent. The potential antineoplastic effect of ACs was investigated in patients who received radiotherapy for localized prostate cancer.

Opportunities and Challenges in the Era of Molecularly Targeted Agents and Radiation Therapy

The first annual workshop for preclinical and clinical development of radiosensitizers took place at the National Cancer Institute on August 8-9, 2012. Radiotherapy is one of the most commonly applied and effective oncologic treatments for solid tumors. It is well recognized that improved clinical efficacy of radiotherapy would make a substantive impact in clinical practice and patient outcomes. Advances in genomic technologies and high-throughput drug discovery platforms have brought a revolution in cancer treatment by providing molecularly targeted agents for various cancers. Development of predictive biomarkers directed toward specific subsets of cancers has ushered in a new era of personalized therapeutics. The field of radiation oncology stands to gain substantial benefit from these advances given the concerted effort to integrate this progress into radiation therapy. This workshop brought together expert clinicians and scientists working in various disease sites to identify the exciting opportunities and expected challenges in the development of molecularly targeted agents in combination with radiation therapy.

Atypical Meningiomas: Recurrence, Reoperation, and Radiotherapy.

INTRODUCTION Atypical meningiomas (World Health Organization [WHO] grade II) represent a therapeutic challenge given their high recurrence rate and greater mortality compared with WHO grade I meningiomas. Traditionally, treatment has entailed attempts at gross total resection with radiation therapy reserved for residual disease or recurrences. METHODS We retrospectively reviewed our patient database of atypical meningioma (AM) patients over the past 10 years to assess surgical and radiotherapeutic treatments administered, treatment-related complications, radiographic-clinical progression after treatment, and mortality. We identified 45 patients with AMs and excluded 2 patients with incomplete hospital records. RESULTS The average age of our patients was 59.7 years. Forty-three AM patients underwent a total of 62 surgeries. Thirty patients underwent one initial surgical resection; 8 patients underwent a second resection for recurrence; 4 patients underwent 3 resections; and 1 patient underwent 4 resections for recurrences. The rate of postoperative complication was 12.9% (8/62). Five patients had postoperative wound infections requiring treatment, and 1 patient had a postoperative hematoma requiring surgical evacuation. There was 1 case of wound breakdown in a patient with a previously irradiated scalp and 1 case of lower-extremity venous thrombosis. Clinical follow-up ranged from 11-120 months with average follow-up of 43 months and median follow-up of 65 months. Nineteen patients (44%) developed clinical-radiographic evidence of recurrence at an average of 32.4 months after surgical resection. Of the recurrences, 12 were treated with repeat surgery and radiation therapy, 3 were treated with radiation therapy alone, and 2 with surgery alone. Radiation therapy included Gamma Knife (GK), CyberKnife (CK), intensity-modulated radiation therapy (IMRT), or some combination of these. There was one case of symptomatic radiation necrosis (1/15 or 6.6%). The survival rate at last follow-up of our patient cohort was 95.3%. CONCLUSIONS Given their high rates of recurrence, AMs require close clinical follow-up and an individualized treatment strategy. Reoperation, radiotherapy, or combination therapy can be effective strategies at managing disease progression while minimizing treatment-related morbidity. Treatment planning that attempts to anticipate future therapies in the form of further surgery or radiotherapy may improve clinical outcomes in these patients. Seventeen patients underwent adjuvant radiation therapy: 7 patients with intensity-modulated radiation therapy (IMRT), 4 patients with Gamma Knife (GK), and 2 with CyberKnife (CK). Four patients underwent multiple treatments.

Aspirin improves outcome in high risk prostate cancer patients treated with radiation therapy

Purpose High-risk prostate cancer (PC) has poor outcomes due to therapeutic resistance to conventional treatments, which include prostatectomy, radiation, and hormone therapy. Previous studies suggest that anticoagulant (AC) use may improve treatment outcomes in PC patients. We hypothesized that AC therapy confers a freedom from biochemical failure (FFBF) and overall survival (OS) benefit when administered with radiotherapy in patients with high-risk PC. Materials and Methods Analysis was performed on 74 high-risk PC patients who were treated with radiotherapy from 2005 to 2008 at UT Southwestern. Of these patients, 43 were on AC including aspirin (95.6%), clopidogrel (17.8%), warfarin (20%), and multiple ACs (31.1%). Associations between AC use and FFBF, OS, distant metastasis, and toxicity were analyzed. Results Median follow-up was 56.6 mo for all patients. For patients taking any AC compared with no AC, there was improved FFBF at 5 years of 80% vs. 62% (P = 0.003), and for aspirin the FFBF was 84% vs. 65% (P = 0.008). Aspirin use was also associated with reduced rates of distant metastases at 5 years (12.2% vs. 26.7%, P = 0.039). On subset analysis of patients with Gleason score (GS) 9–10 histology, aspirin resulted in improved 5-year OS (88% vs. 37%, P = 0.032), which remained significant on multivariable analysis (P < 0.05). Conclusions AC use was associated with a FFBF benefit in high-risk PC which translated into an OS benefit in the highest risk PC patients with GS 9–10, who are most likely to experience mortality from PC. This hypothesis-generating result suggests AC use may represent an opportunity to augment current therapy.

A Retrospective Analysis of Tumor Volumetric Responses to Five-Fraction Stereotactic Radiotherapy for Paragangliomas of the Head and Neck (Glomus Tumors)

Background: Skull base paragangliomas (SBP) are locally expansile tumors that can be treated with stereotactic radiotherapy with favorable results. This report describes the results of 31 patients with SBP treated with CyberKnife radiotherapy delivering a total dose of 25 Gray in five fractions. Methods: All patients treated with five-fraction CyberKnife radiotherapy at a single institution were identified between 2007 and 2013. Tumor volumetric analyses were performed to assess responses to radiotherapy. Results: Median follow-up was 24 months with a range of 4-78 months. Local control and overall survival were 100%. Of the 20 patients who presented with tinnitus, 12 reported improvement (60%), of whom 6 reported complete resolution. There was a 37.3% reduction in tumor volume among all patients (p = 0.16). On subset analysis of patients with ≥24 months of follow-up, tumor volume decreased 49% (p = 0.01). The rate of grade 1-2 toxicity was 19%, with no grade 3 or worse toxicity. Conclusion: A five-fraction CyberKnife-based stereotactic radiotherapy approach is safe and efficacious for the management for patients with SBP. Our findings suggest the potential use of this strategy as a definitive or salvage treatment option for SBP.